Nanocarriers and Diabetes: New Vistas and the Way Ahead.

World Health Organization has reported an estimated 1.5 million deaths directly due to diabetes in 2019. Center for Disease Control and Prevention, in its National Diabetes Statistics Report, 2020, says that 1 in 10 United States residents has diabetes. This rapid progression of diabetes is noteworthy despite significant advances in the field of antidiabetic medicine. The critical challenges in treatment are dyslipidemia, hyperinsulinemia, and hyperglycemia. The latest research has also linked diabetes to carcinogenesis. The diabetic condition accelerates cell growth, proliferation, migration, inflammation, angiogenesis, metastasis, and inhibition of apoptosis in cancer cells. In addition, diabetic complications of nephropathy, retinopathy, neuropathy, cardiomyopathy, peripheral arterial disease, coronary artery disease, and stroke increase morbidity. Amidst all these challenges, a ray of hope is the advent of nanocarriers. The nano size helps in the targeted and controlled delivery of drugs. In addition, nanocarrier formulation helps in the delivery of acid-labile and enzyme- labile molecules and plant-based macromolecules via the oral route. Its use in the form of dendrimers, ethosomes, niosomes, transfersomes, and polymeric nanoparticles is established. In addition, different polymers used to formulate nanocarriers are also established for targeting diabetes. Thus, this review aims to compile approaches involving the use of nanocarriers for the betterment of pharmacotherapy of diabetes and to provide a way ahead for researchers in the field.

Increased serotonergic neurotransmission is not responsible for the anticompulsive effect of berberine in a murine model of obsessive-compulsive disorder.

Berberine, an isoquinoline alkaloid, is being extensively explored in several clinical trials for the treatment of metabolic disorder and cancer. It is also reported to be a potent inhibitor of prolyl oligopeptidase, which makes it a potential candidate for the treatment of neuropsychiatric disorders. We have previously shown the potential of berberine in the control of seizures in various murine models of epilepsy, diabetes-induced memory dysfunction, and ethanol-induced hyperexcitability. We have now examined the effects of acute and subchronic (7 days) administration of berberine on a murine model of obsessive-compulsive disorder - the marble-burying behavior of male mice, because berberine administration is reported to increase brain monoamine levels - a desirable endpoint in the treatment of obsessive-compulsive disorder. The studies showed that an acute administration of berberine [1-25 mg/kg, intraperitoneally (i.p.)] dose-dependently inhibited marble burying in male mice without altering locomotor activity. This effect was retained after its subchronic administration. Furthermore, coadministration of a subeffective dose of berberine (1 mg/kg) and fluoxetine (5 mg/kg, i.p.) significantly reduced marble burying in mice. Pretreatment with p-chlorophenylamine (300 mg/kg, i.p. ×3 days), a tryptophan hydroxylase inhibitor and serotonin-depleting agent, completely blocked the effect of fluoxetine on marble burying, whereas it failed to alter the effect of berberine. In conclusion, the findings of the present investigation indicate that the anticompulsive and/or anxiolytic effect of berberine observed in the present investigation may be attributed to its effect on other neurotransmitter systems, such as the nitrergic or the dopaminergic system rather than to increased serotonin turnover in the brain.

Influence of sigma-1 receptor modulators on ethanol-induced conditioned place preference in the extinction-reinstatement model.

Sigma-1 receptor agonists are reported to augment and antagonists block the rewarding effects of drugs of abuse. However, their effect on reinstatement of ethanol-induced conditioned place preference (CPP) has not yet been explored. Therefore, we investigated the ability of 2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate (PRE-084), a sigma-1 receptor agonist, and N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine dihydrobromide (BD-1047), a sigma-1 receptor antagonist, on the acquisition, expression, and reinstatement of ethanol-induced CPP using adult male Swiss mice. BD-1047 (0.1-10 µg/mouse, intracerebroventricularly) dose-dependently blocked the development, expression, and reinstatement of ethanol-induced CPP, and PRE-084 (0.01-10 µg/mouse, intracerebroventricularly) dose-dependently reinstated the extinguished response. These effects of PRE-084 and BD-1047 alone or in combination with ethanol did not influence the motor activity. Therefore, it is concluded that sigma-1 receptor ligands can modulate the acquisition, expression, and reinstatement of conditioned reinforcing effects of ethanol with no reinforcing or aversive influence of their own. The results add to the growing literature on sigma-1 receptor modulation in the pharmacotherapy of ethanol addiction.

Inhibitory influence of mecamylamine on the development and the expression of ethanol-induced locomotor sensitization in mice.

Several evidences have indicated the involvement of neuronal nicotinic acetylcholine receptors (nAChR) in behavioral effects of drugs of abuse, including ethanol. nAChRs are implicated in ethanol-induced behaviors as well as neurochemical responses to ethanol. Recently, it is demonstrated that mecamylamine, a nAChR antagonist blocks cocaine-, d-amphetamine-, ephedrine-, nicotine-, and methylphenidate-induced psychomotor sensitization. However, no reports are available on its role in ethanol-induced psychomotor sensitization. Therefore, an attempt was made to evaluate its effect on ethanol-induced locomotor sensitization using a model previously described by us. The results revealed that acute administration of mecamylamine (1 and 2mg/kg, i.p.) blocked the acute stimulant effect of ethanol (2.0g/kg, i.p.). In addition, treatment with mecamylamine (0.5-2.0mg/kg, i.p.), 30min prior to the challenge dose of ethanol (2.0g/kg, i.p.) dose dependently attenuated expression of sensitization to locomotor stimulant effect of ethanol. Moreover, administration of mecamylamine (1 and 2mg/kg, i.p.) during development (prior to each ethanol injection on days 1, 4, 7, and 10) blocked acquisition as well as expression (day 15) of sensitization to locomotor stimulant effect of ethanol. Mecamylamine per se did not affect locomotor activity. Further, it also did not influence blood ethanol levels and rotarod performance in mice. These results support the hypothesis that neuroadaptive changes in nAChRs may participate in the development and the expression of ethanol-induced locomotor sensitization.

Inhibitory influence of mecamylamine on ethanol withdrawal-induced symptoms in C57BL/6J mice.

Several reports show the involvement of neuronal nicotinic acetylcholine receptors (nAChRs) in the behavioral effects of ethanol, including ethanol drinking and relapse. Therefore, this study evaluated the effects of mecamylamine, a nAChR antagonist, on ethanol withdrawal signs. Ethanol dependence was induced in C57BL/6J mice by ethanol liquid diet administration. Animals were provided with nutritionally balanced control liquid diet (600 kcal/l) as their sole nutrient source on day 0; from days 1 to 4, 3% v/v of ethanol, followed by 6% v/v of ethanol (from days 5 to 7), and 10% v/v of ethanol (from days 8 to 10) were incorporated into the liquid diet. On day 11, ethanol liquid diet was replaced with nutritionally balanced control liquid diet, and ethanol withdrawal-induced physical signs were recorded. Results showed that acute administration of mecamylamine (1-4 mg/kg, intraperitoneally) dose-dependently attenuated ethanol withdrawal-induced signs, and these effects were comparable with those of diazepam (1-2 mg/kg, intraperitoneally). In addition, chronic administration of mecamylamine into ethanol diet-fed mice markedly attenuated the ethanol withdrawal sign scores, thus supporting the contention that nAChR is involved in ethanol dependence. In conclusion, our results suggest that mecamylamine exhibited inhibitory effects on ethanol withdrawal signs which could be mediated through nAChR.

Effects of central administration of gonadotropin-releasing hormone agonists and antagonist on elevated plus-maze and social interaction behavior in rats.

The correlation between neuronal mechanism of anxiety and neuroanatomic expression/neuromodulatory role of gonadotropin-releasing hormone (GnRH), points to a role of GnRH in the modulation of anxiety. Therefore, we investigated the influence of GnRH agonists and antagonist on the anxiety-like behavior of rats in the elevated plus-maze and social interaction tests. GnRH agonists, leuprolide [100 or 200 ng/rat, intracerebroventricularly (i.c.v.)] or 6-D-tryptophan luteinizing hormone-releasing hormone (400 ng/rat, i.c.v.), significantly increased percentage of open arms entries, time spent in open arms, and time spent in social interaction. The observed anxiolytic effect of these agents was comparable with diazepam (0.5-1.0 mg/kg, intraperitoneally). Treatment with a GnRH antagonist [pGlu-D-Phe-Trp-Ser-Tyr-D-Ala-Leu-Arg-Pro-Gly-NH2, (100 ng/rat, i.c.v.)], significantly reduced percentage of open arm indices and decreased time spent in social interaction, indicating an anxiogenic-like effect. Further, castrated rats exhibited anxiogenic-like behavior in these tests, which was significantly attenuated by leuprolide (200 ng/rat, i.c.v.) or 6-D-tryptophan luteinizing hormone-releasing hormone (400 ng/rat, i.c.v.), indicating the noninvolvement of peripheral sex hormone in their anxiolytic-like effect, at least in castrated rats. In conclusion, this study indicated a putative role of GnRH in the control of anxiety, and further adds to the importance of investigating the possible role of the hypothalamus-pituitary-gonadal axis in regulating the anxiety-related disorders arising out of hypothalamus-pituitary-adrenal axis dysregulation.

Quercetin pretreatment increases the bioavailability of pioglitazone in rats: involvement of CYP3A inhibition.

Herbal antidiabetic preparations are often used as an add-on therapy in diabetes and such herbal preparations often contains quercetin that can inhibit cytochrome P450 (CYP) 3A4. This enzyme is responsible for metabolizing pioglitazone, a commonly used antidiabetic agent. Hence, it was speculated that quercetin may influence the bioavailability of pioglitazone, which could be particularly crucial, as any increment in its plasma levels may raise safety concerns. Thus, we first established the inhibitory influence of quercetin (2, 10 and 20 mg/kg, p.o.) on CYP3A activity by an in vivo method of estimating levels of midazolam in female rats pretreated with dexamethasone. It was further confirmed in vitro using erythromycin-N-demethylase (EMD) assay. These studies indicated potent inhibition of CYP3A activity by quercetin (10 and 20 mg/kg, in vivo; 1 and 10 microM, in vitro). In another experiment, pioglitazone was administered orally (10 mg/kg) and intravenously (5mg/kg) to quercetin (10 mg/kg) pretreated female rats and its plasma levels were determined at various time points (0.5, 1, 2, 4, 8 and 24 h after oral administration; 0.083, 0.5, 1, 2, 8, 12 and 18 h after i.v. administration) by HPLC. Quercetin pretreatment increased AUC(0-infinity) of pioglitazone after oral administration by 75% and AUC(0-infinity) after intravenous administration by 25% suggesting decreased metabolism, which could be due to inhibition of CYP3A by quercetin. In conclusion, add-on preparations containing quercetin may increase the bioavailability of pioglitazone, and hence should be cautiously used.